Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions

• 成果类型: Article
• 署名作者: Ma, Weikang; del Rio, Carlos L.; Qi, Lin; Prodanovic, Momcilo; Mijailovich, Srboljub; Zambataro, Christopher; Gong, Henry; Shimkunas, Rafael; Gollapudi, Sampath; Nag, Suman; Irving, Thomas C.
• 署名单位: Illinois Institute of Technology; Illinois Institute of Technology; Bristol-Myers Squibb; Illinois Institute of Technology; University of Kragujevac
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13290
• DOI: 10.1073/pnas.2314914121
• 发表日期: 2024-02-20
• 关键词: hypertrophic cardiomyopathy; skeletal-muscle; molecule; contractility; pathogenesis; diffraction

摘要

Mavacamten is a FDA- approved small- molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered offstates close to the thick filament backbone. It remains elusive whether these myosin heads in the offstate(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these offstate(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) fl- adrenergic (fl - AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca2+ increases myosin ATPase activity by shifting mavacamten- stabilized myosin heads from the inactive super- relaxed state to the active disordered relaxed state. At the myofilament level, both Ca2+ and passive lengthening can shift mavacamten- ordered offmyosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten- treated cells. This observation was confirmed in vivo in telemetered rats, where left- ventricular dP/dtmax, an index of inotropy, increased with HR in mavacamten- treated animals. Finally, we show that fl - AR stimulation in vivo increases left- ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten- promoted offstates of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.